PERSPECTIVE PERSPECTIVE Antibody persistence and T-cell balance: Two key factors confronting HIV vaccine development George K. Lewis1, Anthony L. DeVico, and Robert C. Gallo1 Division of Basic Science and Vaccine Research Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 Edited by Anthony S. Fauci, National Institute of Allergy and Infectious Diseases, Bethesda, MD, and approved September 5, 2014 (received for review July 21, 2014) The quest for a prophylactic AIDS vaccine is ongoing, but it is now clear that the successful vaccine must elicit protective antibody responses. Accordingly, intense efforts are underway to identify immunogens that elicit these responses. Regardless of the mechanism of antibody- mediated protection, be it neutralization, Fc-mediated effector function, or both, antibody persistence and appropriate T-cell help are significant problems confronting the development of a successful AIDS vaccine. Here, we discuss the evidence illustrating the poor persistence + of antibody responses to Env, the envelope glycoprotein of HIV-1, and the related problem of CD4 T-cell responses that compromise vaccine efficacy by creating excess cellular targets of HIV-1 infection. Finally, we propose solutions to both problems that are applicable to all Env- based AIDS vaccines regardless of the mechanism of antibody-mediated protection. HIV | vaccine | antibody persistence | AIDS | Tcell HIV vaccine development presents unprece- 17). A large body of data points toward a role exhibited efficacy. The protection was mod- dented challenges on multiple levels, a reality, for antibody responses to the HIV envelope est, with an overall of efficacy 31.2% (21) in often overlooked, that cannot be overstated. glycoprotein (Env) in sterilizing protection one of three subgroup analyses. Specifically, + The chief challenge is that HIV is a human against HIV. A beneficial role for CD8 T this subgroup analysis was the modified retrovirus that replicates by irreversibly cells in blocking acquisition is less apparent, intention-to-treat analysis, which excluded inserting its genes into the host genome. although this possibility cannot be dismissed. seven volunteers in the trial who were found + Thus, HIV infection is established perma- Intriguing studies suggest that CD8 T-cell to have HIV infection before vaccination be- nently in a matter of days or perhaps even responses elicited by a replicating viral vector gan (additional statistical considerations sup- hours (1–6), and it cannot be cleared by pri- vaccine can clear a nascent simian immuno- porting vaccine efficacy in the RV144 trial are mary or anamnestic responses that occur af- deficiency virus (SIV) infection in roughly discussed in ref. 24). Protection correlated ter exposure. In addition to integrating into half of vaccinated nonhuman primates (18). with antibodies against the V1/V2 region of the host genome, a second unique challenge These responses alone did not block acquisi- gp120 (25), particularly those antibodies of + is that HIV replicates in CD4 T cells that are tion but could contribute to such an effect if the IgG3 subclass that mediate potent anti- key players in protective immunity not only combined with certain humoral responses. body-dependent cellular cytotoxicity (ADCC) to HIV itself (7–9) but also to many other These responses could be neutralizing, Fc (26), in addition to other aspects of anti-gp120 pathogens (cf. ref. 10). These central features receptor-dependent, or both. This viewpoint humoral immunity (25–29). Importantly, ef- distinguish the path to an HIV vaccine from is driven by several considerations: an ex- ficacy in the RV144 trial was temporally the traditional design principles that led to panding body of evidence linking antibody dependent, peaking at ∼59.9% early in the successful vaccines against other infectious responses with protection (reviewed in ref. study and waning to background by the agents. The inability of these principles to 19); increasingly detailed structural informa- end of the 3-y postvaccination follow-up, yield an HIV vaccine became abundantly tion regarding anti-Env mAbs (cf. ref. 20); thus producing an overall efficacy of 31.2% clear in six large HIV vaccine trials, where and the modest success of the RV144 trial, (30). Why did efficacy decline in this study? efficacy was not observed (11–16) (Table 1). where an antibody response correlated with The most probable answer is that the anti- Strikingly, vaccination increased the risk of reduced infection risk (21) (Table 1). Para- gp120 responses linked with efficacy did not infection in two of these studies that selec- doxically, this realization introduces another persist, as shown by Yates et al. (26). In this tively targeted T-cell immunity (13–15), major challenge: Antibody responses to light, had the antibody titers responsible for providing a stark contrast between the de- gp120-based vaccines persist poorly in hu- 59.9% protection in the RV144 trial been velopment of conventional and HIV vac- mans or other mammalian species (reviewed cines. Against this backdrop, what will it in ref. 22). The point is moot whether this Author contributions: G.K.L., A.L.D., and R.C.G. designed research, take to develop the first protective vaccine problem is unique to HIV gp120 or extends performed research, and wrote the paper. against a human retrovirus? to responses against other viral vaccines, as Conflict of interest statement: The authors own stock in ThenatureofHIVinfectionargues suggested for the influenza virus hemaggluti- Profectus Biosciences. strongly that an effective vaccine must block nin (23); it must be solved for an effective This article is a PNAS Direct Submission. infection such that it never becomes estab- HIV vaccine. The importance of this issue Freely available online through the PNAS open access option. lished in vaccinated individuals (i.e., steriliz- is immediately apparent in HIV vaccine trials 1To whom correspondence may be addressed. Email: glewis@ihv. ing protection) (17). Critically, this protection involving Env. As shown in Table 1, there umaryland.edu or [email protected]. must persist because there will not be time have been six HIV vaccine efficacy trials of This article contains supporting information online at www.pnas.org/ for a recall response to block infection (1–6, four vaccine concepts; only the RV144 trial lookup/suppl/doi:10.1073/pnas.1413550111/-/DCSupplemental. www.pnas.org/cgi/doi/10.1073/pnas.1413550111 PNAS Early Edition | 1of8 Downloaded by guest on September 26, 2021 Table 1. HIV vaccine efficacy trials with controls (46). More recent studies sug- + + Vaccine concept Trial no. Study population Outcome Ref(s). gest that the number of CD4 CCR5 T cells at the site of mucosal HIV exposure is a Clade B gp120 subunit/alum VAX 003 IVDU, Thailand, high risk No efficacy (10) key determinant of transmission. For ex- Clade B gp120 subunit/alum VAX 004 MSM, heterosexual; North No efficacy (9) ample, mother-to-infant SIV transmission is America, The Netherlands; attenuated in the natural SIV host, sooty high risk + mangabeys, due to a dearth of CD4 Clade B, gag, pol, nef Ad5 HVTN-504 MSM; Americas, Caribbean, No efficacy, (11) + (T-cell vaccine) (Step) Australia; high risk increased CCR5 T cells in secondary lymphoid tissue transmission of the infants (47). By contrast, mother-to- Clade B, gag, pol, nef Ad5 HVTN-503 Heterosexual, South Africa, No efficacy, (12) infant transmission of SIV occurs more (T-cell vaccine) (Phambili) high risk increased readily in rhesus macaques and correlates transmission with the increased frequencies and prolifer- Clade A/E gp120, gag, pol RV144 Heterosexual, some MSM/IVDU; 31.2% overall (17) ative potential of these cells in secondary Canarypox (ALVAC) prime Thailand; community-based efficacy, 59.9% lymphoid tissue of the infants (47). and three boosts; two risk; 47.5% low risk, 28.4% early efficacy, The increased transmission associated with additional boosts with moderate risk, 24.1% high risk waning to unappreciated immune activation in Ad5- ALVAC plus clade B/E background by HIV efficacy trials is abundantly apparent in gp120s in alum study end the follow-up to the HIV Vaccine Trials Clade A, B, and C env plus HVTN-505 MSM, USA, high risk No efficacy (14) clade B gag, pol DNA-prime; Network 503 (HVTN-503; Phambili) (14, 15) clade A, B, and C env plus and HVTN-504 (Step) (13, 48) trials, in clade B gag, pol Ad5 boost which vaccinees experienced a higher and (antibody and T-cell vaccine) sustained increased risk of infection com- pared with placebo recipients (15, 48). Be- IVDU, intravenous drug users; MSM, men who have sex with men. cause the vaccines tested in these trials did not include the HIV envelope, any impact of + maintained, the vaccine could be licensable help by CD4 Tfhs, which are also reservoirs T-cell activation would be relatively unbri- theoretically, at least for use in Thailand. of HIV infection (31–33). Curiously, al- dled. Based on the above observations, it is + In this context, it should be noted that though CD4 Tfhs are infected by HIV, they highly likely that some aspect of immune the RV144 study population was enrolled lack the principal HIV coreceptor, C-C che- activation related to the use of Ad5 vectors without regard to risk of HIV infection (i.e., mokine receptor type 5 (CCR5), that is used in the vaccine led to the increased risk of community risk) and was composed of low- by transmitted founder viruses (37). It is infection. There is evidence that prevaccina- risk (47.5%), moderate-risk (28.4%), and likely that they are infected at an earlier, tion anti-Ad5 titers correlated with altered + high-risk (24.1%) subjects (21). By contrast, CCR5 , stage in Tfh development, as indi- early innate responses to the vaccine (49). Further, there is evidence that Ad5 immuni- the five ineffective trials in Table 1 recruited cated by Xu et al.